Dual Synergistic Tumor‐Specific Polymeric Nanoparticles for Efficient Chemo‐Immunotherapy

Abstract Chemo‐immunotherapy has made significant progress in cancer treatment. However, the cancer cell self‐defense mechanisms, including cell cycle checkpoint and programmed cell death‐ligand 1 (PD‐L1) upregulation, have greatly hindered the therapeutic efficacy. Herein, norcantharidin (NCTD)‐platinum (Pt) codelivery nanoparticles (NC‐NP) with tumor‐sensitive release profiles are designed to overcome the self‐defense mechanisms via synergistic chemo‐immunotherapy. NC‐NP remains stable under normal physiological conditions but quickly releases 1,2‐diaminocyclohexane‐platinum(II) (DACHPt, a parent drug of oxaliplatin) and NCTD in response to the tumor acidity. NCTD inhibits protein phosphatase 2A (PP2A) activity to relieve cell cycle arrest and downregulates the tumor PD‐L1 expression to disrupt the programmed cell death‐1 (PD‐1)/PD‐L1 interaction, synergistically enhancing Pt‐based chemotherapy and immunogenic cell death‐induced immunotherapy. As a result, NC‐NP exhibits potent synergistic cytotoxicity and promotes T cell recruitment to generate robust antitumor immune responses. The dual synergism exhibits potent antitumor activity against orthotopic 4T1 tumors, providing a promising chemo‐immunotherapy paradigm for cancer treatment.